Synthesis of S-Aryl Phosphorothioates by Copper-Catalyzed

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Synthesis of S-Arylphosphorothioates by Copper-Catalyzed Phosphorothiolation of Diaryliodonium and Arenediazonium Salts Liangliang Zhang, Pengbo Zhang, Xueqin Li, Jian Xu, Guo Tang, and Yufen Zhao J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b00925 • Publication Date (Web): 31 May 2016 Downloaded from http://pubs.acs.org on June 1, 2016

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The Journal of Organic Chemistry

Synthesis

of

S-Arylphosphorothioates

by

Copper-Catalyzed

Phosphorothiolation of Diaryliodonium and Arenediazonium Salts Liangliang Zhang,† Pengbo Zhang,† Xueqin Li,† Jian Xu,*,‡ Guo Tang,*,† and Yufen Zhao† †

Department of Chemistry, College of Chemistry and Chemical Engineering, and the Key Laboratory for Chemical Biology of Fujian Province, Xiamen University, Xiamen 361005, China

Fax: (86)592-2185780; [email protected] ‡

Institute of Next Generation Matter Transformation, College of Chemical Engineering, Huaqiao

University, Xiamen 361021, China [email protected] RECEIVED DATE (will be automatically inserted after manuscript is accepted).

Green methods for the synthesis of S-arylphosphorothioates have been developed based on copper catalyzed multicomponent reactions involving diaryliodonium/arenediazonium salts, elemental sulfur, and R2P(O)H compounds. Most target products are obtained with these two methods in good to high yields at room temperature. These transformations allow the direct formation P−S and C−S bonds in

one reaction.

INTRODUCTION

Compounds incorporating phosphorus−sulfur bond are versatile reagents in both organic and inorganic synthesis. The best known example, Lawesson’s reagent [(4-MeOC6H4)P=S (µ-S)]2, is widely used in organic chemistry, for example, for the conversion of C=O to C=S groups.1

ACS Paragon Plus Environment


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Phosphate esters have broad applications in the fields of pharmaceuticals and agrochemicals owing to its unique properties. Among the phosphate esters, phosphorothioates have received considerable attention for more than 60 years because of their biological properties, for example, as pesticides, insecticides, enzyme modifiers, and potential HIV-1 and ACHE inhibitors.2 Additionally, S-aryl phosphorothioates are also key synthetic intermediates for a variety of complex molecules.3 In contrast to the P=S functionality, the synthesis of analogues bearing sulfur atom at the bridging position of a phosphate group as in a C–S–P(O) functionality, is usually a more complicated task. Traditional synthesis work of S-aryl phosphorothioates often proceeds via the reaction

between

arylthiols

and

phosphorylation

reagents

(phosphorochloridates

and

phosphorobromidates), however, chlorine and bromine are both toxic and difficult to control, besides the preparation of phosphorochloridates and phosphorobromidates is required (Scheme 1a).4 As we know, thiols emit a pungent odour during and after use. Various substituted arylsulfides (disulfides, sulfuryl chloride, and sulfonylhydrazides) instead of thiophenol were well developed to construct C–S–P(O) bonds (Scheme 1b).5 In 2009, our group reported the direct coupling of readily available R2P(O)H compounds with diaryl disulfides in the presence of catalytic amounts of copper iodide.5b Recently, we successfully developed a facile catalytic method for the preparation of S-aryl phosphorothioates via phosphorothiolation of aryl boronic acids with R2P(O)H compounds and sulfur powder (Scheme 1c).6 Hence, there is still great need for the development of a convenient protocol to produce various phosphorothioate derivatives.

Scheme 1. C(aryl)−S−P Bond-Forming Reactions


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previous work ArSH

+

O Ar S P OR OR

O RO P X RO X = Cl, Br

O RO Ar-X + P H or (RO)3P RO

Ar

O S P OR OR

(a)

(b)

X = SH, SCl, SPh, SO2NHNH2, SO2Cl our previous work Ar B(OH)2 + S8

O RO + P H RO

this work OTf 1 I O Ar Ar2 RO S + + P H or 8 RO Ar1 N2BF4

Ar

O S P OR (c) OR

O Ar1 S P OR (d) OR

Diaryliodonium salts, as important and valuable electrophilic arylation reagents, have recently received considerable attention due to their high reactivity and nontoxicity.7 The regioselective preparation of arylphosphonates using unsymmetrical diaryliodonium salts was discovered by our group in 2013.8 Moreover, owing to the efforts of Beringer, Olofsson, and others, symmetrical and unsymmetrical diaryliodonium triflates can now be easily synthesized from both electron-deficient and electron-rich arenes and aryl iodides with mCPBA and triflic acid in one pot.9 Furthermore, diaryliodonium salts are stable and can be stored for one year or more at room temperature. On the other hand, in comparison with those aforementioned sulfur species, sulfur powder (S8) is cheap and more abundant in nature.10 Utilization of common and readily available chemicals as the components and involvement of selective formation of C(aryl)–S–P bond should make this reaction much more attractive. Herein we report a novel and efficient one-step synthesis of S-aryl phosphorothioates via multicomponent coupling of diaryliodonium salts, elemental sulfur (S8), and R2P(O)H compounds (Scheme 1d).



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RESULTS AND DISCUSSION

Table 1. Optimization of Reaction Conditionsa

a

entry

catalyst

base

solvent

yield (%)

1

Cu(OAc)2

Et3N

CH3CN

92

2

Cu(OTf)2

Et3N

CH3CN

75

3

Cu(acac)2

Et3N

CH3CN

100a,b (95)a,c

4

CuCl

Et3N

CH3CN

70

5

CuI

Et3N

CH3CN

44

6

Cu2O

Et3N

CH3CN

66

7

-

Et3N

CH3CN

0

8

Cu(acac)2

K2CO3

CH3CN

86

9

Cu(acac)2

Cs2CO3

CH3CN

85

10

Cu(acac)2

NaOAc

CH3CN

38

11

Cu(acac)2

K3PO4

CH3CN

70

12

Cu(acac)2

Et3N

THF

89

13

Cu(acac)2

Et3N

DMF

80

14

Cu(acac)2

Et3N

toluene

95a, 35d

Reaction

conditions:

diphenyliodonium

triflate

(0.30

mmol),

diethyl

H-phosphonate (0.30 mmol), elemental sulfur (0.45 mmol, 14.4 mg), catalyst (0.03 mmol), base (0.45 mmol), solvent (1.5 mL) in a 10 mL tube at room temperature for 20 h in air. Yield determinined by

31

P NMR. Values in

b

parentheses indicate yield after purification. 1.0 equivalents of TEMPO was added. c2,2’-bipyridine (0.06 mmol) was added as ligand, reaction time: 5 h. under a nitrogen atmosphere.


d

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As an initial attempt, reacting diphenyliodonium triflate (1a, 0.30 mmol) with elemental sulfur (2, 0.45 mmol, 14.4 mg) and diethyl H-phosphonate (3a, 0.30 mmol) in the presence of Cu(OAc)2 as catalyst and Et3N as base under air in CH3CN at room temperature were investigated. Pleasingly, the reaction provided the product 4a in 92% yield (Table 1, entry 1). Without sulfur powder, P-arylation product could be obtained in 70% yield within 10 min.8 Once sulfur powder was added, P-arylation could be completely suppressed. Subsequently, various Cu(II) and Cu(I) salts were further checked and the results showed that Cu(II) salts were more effective to give the desired product (entries 1-6). Cu(acac)2 showed the highest activity and gave 4a in almost quantitative yield within 20 hours (entry 3a). When 2,2’-bipyridine was added as ligand, the reaction could be completed in 5 h (entry 3b). No desired product was afforded without copper salt (entry 7). Other inorganic bases, such as K2CO3, Cs2CO3, NaOAc and K3PO4 , could also execute this reaction but with lower efficiency (entries 8-11). In addition to CH3CN, other tested solvents, such as THF, DMF, and toluene, all gave good yields. Other inorganic sulfides such as Na2S2O3, K2S2O8, K2S instead of elemental sulfur were investigated. K2S was also effective, giving the product 4a in 50% yield. The same yield was obtained when 1.0 equiv of TEMPO was added in the reaction under the optimal conditions (entry 3c). Reactions performed under a nitrogen atmosphere led to a 35% yield (entry 14d). These results suggest that the mechanism is like the well-known Chan−Evans−Lam coupling reaction.6 With the optimized conditions in hand, the generality of the method was explored under the optimized conditions (Table 1, entry 3a), and the results are summarized in Scheme 2. First, symmetrical iodonium salts with electron-donating groups such as methyl, tert-butyl and methoxy all afforded the desired products (4b-4e) in good yields. Gratefully, steric bulk posed no problem



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in this reaction, as exemplified by 2,5-dimethyl product 4d. In regard to the H-phosphonates, in addition to diethyl H-phosphonate, dibenzyl, dimethyl, and diisopropyl all could be used as the substrates, generating the corresponding S-aryl phosphorothioates in 71-85% yields (4f-4h). When ethyl phenylphosphinate was used, 4i was obtained in 74% yield. Diphenylphosphine oxide was used in the phosphorothiolation of iodonium salt, and led to the formation of product 4j in 65% yield indicating that the reactivities of these P(O)–H compounds are almost independent of the alkoxy and alkyl moieties. Symmetrical iodonium salts with electron-withdrawing groups were less effective, giving the corresponding products 4k-4o in 10- 40% yields. Raising temperature to 60 oC slightly increase the yield. We then designed unsymmetrical diaryliodonium salts with one mesityl group and one electron-deficient aryl group. 4-Fluoro-, 4-chloro- and 4-bromophenyliodonium triflates were examined for the reactivity with diethyl H-phosphonate and sulfur powder under the same reaction conditions to give the expected products 4k-4m in excellent yields. Unsymmetrical iodonium salts with electron-withdrawing groups such as 4-acyl and 3-trifluoromethyl afforded 4n and 4o with satisfactory results. Substituted phenyl ring with electron-donating o-methyl, p-methyl and p-phenyl groups of the salts reacted with diethyl H-phosphonate and sulfur powder to result in the corresponding S-aryl phosphorothioates (4p-4r) in 70-84% yields. Unsymmetrical iodonium salts with pyridine group didn’t work in this method.


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Scheme 2. Scope of Phosphorothiolation of Iodonium Salts. I

OTf R2 + S8

R1 1

2

O P OEt OEt

S

R1 O Cu(acac)2 (10 mol %) , Et3N R3 + PH R4 CH3CN, rt, 20 h 3

S

4a 95%

4b 85%

O P OEt t-Bu OEt

O S P R4 3 4a-4r R

O P OEt OEt

S 4c 81%

O P OEt OEt 4d 70%

S

OTf I R1

MeO

R1

4e 70% symmetrical iodonium salts 1a-1e as starting materials for 4a-4j O O S P OMe S P O-i-Pr OMe O-i-Pr 4h 71% 4g 80%

F

S

O P OEt OEt

Cl

4k 90% OTf

4l 87%

1

H3C

S 4i 74%

CH3

unsymmetrical iodonium salts 1f-1n as starting materials for 4k-4r O S P OEt OEt 4p 73%

S

4n 94%

O S P Ph Ph 4j 65%

O P Ph OEt

O S P OEt OEt

EtO2C

O P OBn OBn

S 4f 85%

CH3

I R

O S P OEt OEt

O P OEt OEt

O S P OEt OEt 4q 84%

Br

S 4m 88%

F3C

S 4o 87%

O P OEt OEt

O P OEt OEt

O S P OEt OEt 4r 70%

Encouraged by the findings described above, we continued to explore the synthesis of S-aryl phosphorothioates from diazonium salts. As we know, diazonium compounds are standard reagents used in synthesis of organic compounds, especially aryl derivatives.11 Arenediazonium cations are very versatile and useful synthons and show the several reactions in which the N2 group is replaced by another group or ion.12 Furthermore, the preparation of arenediazonium tetrafluoroborate salts is treatment of cheap aromatic amines with sodium nitrite in the presence of



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tetrafluoroboric acid. The pure arenediazonium tetrafluoroborate salts are stable at room temperature and can be stored below 8 °C for several months. To our delight, when diazonium tetrafluoroborates was employed as the aryl source, the reaction took place under slightly modified conditions. The optimal reaction conditions are: 1) Cu(OTf)2 (0.06 mmol), R2P(O)H (0.30 mmol), elemental sulfur (0.45 mmol), Et3N (0.45 mmol), in CH3CN (1.0 mL) for 20 min; 2) adding arenediazonium salt (0.36 mmol, in CH3CN 0.5 mL) into the above reaction mixture and stirring at room temperature for 12 h. No 4a was obtained when 1.0 equiv of TEMPO was added. The yield of 4a was decreased to 10% when the reaction was performed in the open air. Although the detailed mechanism remains ambiguous at present, we reasoned that directly generating S-hydrogen phosphorothioate by reaction of R2P(O)H and elemental sulfur would react with arenediazonium salt leading to the formation of S-aryl phosphorothioates via a radical pathway in the presence of copper catalyst.6,13 We next examined the reactions of various substituted arenediazonium tetrafluoroborates 5 with sulfur powder and R2P(O)H compounds to probe the scope of the reaction (Scheme 3). It was found that a wide range of arenediazonium tetrafluoroborates proceeded efficiently. With methyl substituted on benzene, such as para-, meta-, and ortho-methyl groups (5b-5d), these compounds reacted efficiently to give the desired products in good yields. Halogen atoms such as fluorine, chlorine, bromine, and iodine (5e-5k) have little influence under the optimized reaction conditions to afford the corresponding products in moderate to good yields. The ortho-substituted diazonium salts gave much lower yields because of the steric effect (5c, 5h-5j).


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Scheme 3. Scope of Phosphorothiolation of Diazonium Salts.



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Diazonium salts with electrondonating (methoxy) or electron-withdrawing (CN, CH3CO, CF3, NO2, COOEt, and CONH2) groups all produced the desired products in good yields, suggesting that the substituted groups did not have a significant influence on the reaction (5l-5r). In regard to the H-phosphonates, in addition to 3a, dibenzyl (3b), dimethyl (3c), and diisopropyl (3d) all could be used as the substrates, generating the corresponding S-aryl phosphorothioates (4f–4h) in 70–81% yields. When ethyl phenylphosphinate (3e) was used, 4i was obtained in good yield. Diphenylphosphine oxide was also examined. Unfortunately, only 22% yield of the desired P-S-C bond-forming product was obtained. In order to demonstrate the practical application of these methods, phosphorothiolation of diaryliodonium (5 mmol) and arenediazonium(6 mmol) salts were conducted and afforded 4a in good yields (Scheme 4). Scheme 4. Scale-up Preparation of 4a.

CONCLUSION

In conclusion, we have developed two novel copper-catalyzed phosphorus-sulfur-carbon(aryl) bond-forming reactions which proceeds in good yield via phosphorothiolation of diaryliodonium or diazonium salts with R2P(O)H compounds and sulfur powder. The reactions described provide novel accesses to S-aryl phosphorothioates and cover a broad scope of substrates. Importantly, this


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transformation would provide a new pathway for the formation of P−S and C−S bonds in one reaction. Moreover, the diaryliodonium salts and diazonium salts can be readily prepared from the corresponding cheap arene compounds. In addition, the use of an inexpensive Cu(II) catalyst without any ligands, using readily available sulfur powder (S8) and R2P(O)H compounds, means that this facile protocol will have wide application for the construction of biologically active S-aryl phosphorothioates. EXPERIMENTAL SECTION General. All reagents were purchased and used without further purification. The solvent was freshly distilled. All new compounds were further characterized by HRMS (FT-ICR-MS) and electrospray ionization source in positive ion mode. 1. General Procedure for the Phosphorothiolation of Diaryliodonium Salts (Method A) A 10 mL tube was charged with Cu(acac)2 (0.03 mmol, 7.8 mg), R2P(O)H (0.30 mmol), elemental sulfur (0.45 mmol, 14.4 mg), diaryliodonium triflate (0.30 mmol), Et3N (0.45 mmol, 45.5 mg), and CH3CN (1.5 mL), and the reaction mixture was stirred at room temperature open to air for 20 h. After completion, the crude reaction mixture was purified by flash chromatography using petroleum−AcOEt (3:1, v/v) as the eluent to give S-aryl phosphorothioates. The preparations of symmetrical and unsymmetrical iodonium salts are shown in refs 9d-9g. 2. General Procedure for the Phosphorothiolation of Arenediazonium Salts (Method B) An oven-dried Schlenk tube with a magnetic stir bar containing Cu(OTf)2 (0.06 mmol, 21.7 mg), R2P(O)H (0.30 mmol), elemental sulfur (0.45 mmol, 14.4 mg) was evacuated and purged with nitrogen three times. Et3N (0.45 mmol, 45.5 mg) and CH3CN (1.0 mL) were added to the system at room temperature and the reaction mixture was stirred at room temperature for 20 min. Then, arenediazonium salt (0.36 mmol) in CH3CN (0.5 mL) was added to the system at room



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temperature. The resulting mixture was stirred at room temperature for 12 h. After completion, the crude reaction mixture was purified by flash chromatography using petroleum−AcOEt (3:1, v/v) as the eluent to give S-aryl phosphorothioates. The preparations of arenediazonium salts are shown in ref 11f. O,O-Diethyl S-Phenyl Phosphorothioate (4a) (CAS Registry No. 1889-58-3).6 Yield: 69.8 mg, 95% (Method A); 70.1 mg, 95% (Method B). Yellow oil. 1H NMR (400 MHz, CDCl3, ppm) (Method B) δ 7.58 – 7.55 (m, 2 H), 7.35 – 7.31 (m, 3 H), 4.26 – 4.11 (m, 4 H), 1.32 – 1.28 (m, 6 H). 13C{1H} NMR (100 MHz, CDCl3, ppm) δ 134.6 (d, J = 5.2 Hz), 129.4 (d, J = 2.0 Hz), 129.0 (d, J = 2.6 Hz), 126.6 (d, J = 7.2 Hz), 64.1 (d, J = 6.3 Hz), 16.0 (d, J = 7.1 Hz). 31P{1H} NMR (162 MHz, CDCl3, ppm) δ 22.8. MS-ESI: m/z 268.8, [M + Na]+. O,O-Diethyl S-p-Tolyl Phosphorothioate (4b) (CAS Registry No. 4143-38-8).6 Yield: 66.0 mg, 85% (Method A); 66.3 mg, 85% (Method B). Yellow oil. 1H NMR (400 MHz, CDCl3, ppm) (Method B) δ 7.45 – 7.43 (m, 2 H), 7.15 (d, J = 8.1 Hz, 2 H), 4.26 – 4.11 (m, 4 H), 2.34 (d, J = 1.8 Hz, 3 H), 1.32 – 1.29 (m, 6 H). 13C{1H} NMR (100 MHz, CDCl3, ppm) δ 139.3 (d, J = 3.0 Hz), 134.6 (d, J = 5.0 Hz), 130.1 (d, J = 2.3 Hz), 122.8 (d, J = 7.3 Hz), 64.0 (d, J = 6.1 Hz), 21.2, 16.0 (d, J = 7.3 Hz). 31P{1H} NMR (162 MHz, CDCl3, ppm) δ 23.3. MS-ESI: m/z 282.8, [M + Na]+. S-(4-(Tert-butyl)phenyl) O,O-Diethyl Phosphorothioate (4c). Yield: 73.4 mg, 81% (Method A). Yellow oil. 1H NMR (400 MHz, CDCl3, ppm) δ 7.48 – 7.46 (m, 2 H), 7.35 (d, J = 8.3 Hz, 2 H), 4.26 – 4.13 (m, 4 H), 1.32 – 1.30 (m, 15 H). 13C{1H} NMR (100 MHz, CDCl3, ppm) δ 152.5 (d, J = 3.1 Hz), 134.5 (d, J = 4.9 Hz), 126.6 (d, J = 2.3 Hz), 122.9 (d, J = 7.2 Hz), 64.1 (d, J = 6.1 Hz), 34.8, 31.3, 21.1, 16.1 (d, J = 7.3 Hz).

31

P{1H}NMR (162 MHz, CDCl3, ppm) δ 23.4. HRMS (ESI) m/z: [M + Na]+ Calcd for

C14H23NaO3PS+, 325.0998; Found: 325.0988).


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S-(2,5-Dimethylphenyl) O,O-Diethyl Phosphorothioate (4d) (CAS Registry No. 1628447-77-7).5i Yield: 57.6 mg, 70% (Method A). Yellow oil. 1H NMR (400 MHz, CDCl3, ppm) δ 7.41 (s, 1 H), 7.12 (d, J = 7.9 Hz, 1 H), 7.06 (d, J = 7.9 Hz, 1 H), 4.22 – 4.09 (m, 4 H), 2.47 (s, 3H), 2.30 (s, 3 H), 1.31 – 1.28 (m, 6 H). 13C{1H} NMR (100 MHz, CDCl3, ppm) δ 139.2 (d, J = 5.6 Hz), 136.9 (d, J = 3.9 Hz), 136.4 (d, J = 2.6 Hz), 130.7 (d, J = 2.6 Hz), 130.4 (d, J = 3.3 Hz), 125.3 (d, J = 7.3 Hz), 64.2 (d, J = 6.7 Hz), 21.0, 20.9, 16.1 (d, J = 7.2 Hz). 31P{1H} NMR (162 MHz, CDCl3, ppm) δ 23.4. MS-ESI: m/z 296.9, [M + Na]+. O,O-Diethyl S-(4-Methoxyphenyl) Phosphorothioate (4e) (CAS Registry No. 56806-76-9).5j Yield: 58.0 mg, 70% (Method A); 79.5 mg, 96% (Method B). Yellow oil. 1H NMR (400 MHz, CDCl3, ppm) (Method B) δ 7.48 – 7.46 (m, 2 H), 6.88 (d, J = 8.7 Hz, 2 H), 4.25 – 4.10 (m, 4 H), 3.80 (s, 3 H), 1.33 – 1.29 (m, 6 H). 13C{1H} NMR (100 MHz, CDCl3, ppm) δ 160.5 (d, J = 2.9 Hz), 136.3 (d, J = 4.7 Hz), 116.6 (d, J = 7.5 Hz), 115.0 (d, J = 2.6 Hz), 64.0 (d, J = 6.3 Hz), 55.4, 16.0 (d, J = 7.1 Hz). 31P{1H} NMR (162 MHz, CDCl3, ppm) δ 23.5. MS-ESI: m/z 298.9, [M + Na]+. O,O-Dibenzyl S-Phenyl Phosphorothioate (4f) (CAS Registry No. 1608108-22-0).5c Yield: 94.3 mg, 85% (Method A); 85.5 mg, 77% (Method B). Yellow oil. 1H NMR (400 MHz, CDCl3, ppm) (Method B) δ 7.48 – 7.46 (m, 2 H), 7.30 – 7.23 (m, 13 H), 5.14 – 5.05 (m, 4 H). 13C{1H} NMR (100 MHz, CDCl3, ppm) δ 135.3 (d, J = 7.6 Hz), 134.8 (d, J = 5.3 Hz), 129.4 (d, J = 2.2 Hz), 129.1 (d, J = 2.8 Hz), 128.6, 128.5, 128.0, 125.9 (d, J = 7.3 Hz), 69.4 (d, J = 6.4 Hz). 31P{1H} NMR (162 MHz, CDCl3, ppm) δ 23.9. MS-ESI: m/z 370.9, [M + H]+. O,O-Dimethyl S-Phenyl Phosphorothioate (4g) (CAS Registry No. 4237-00-7). 5j Yield: 52.3 mg, 80% (Method A); 53.0 mg, 81% (Method B). Yellow oil. 1H NMR (400 MHz, CDCl3, ppm) (Method B) δ 7.56 – 7.54 (m, 2 H), 7.38 – 7.32 (m, 3 H), 3.82 (s, 3 H), 3.79 (s, 3 H).


13

C{1H} NMR (100 MHz,


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CDCl3, ppm) δ 134.7 (d, J = 5.4 Hz), 129.6 (d, J = 1.9 Hz), 129.3 (d, J = 3.2 Hz), 126.1 (d, J = 7.4 Hz), 54.3 (d, J = 6.4 Hz). 31P{1H} NMR (162 MHz, CDCl3, ppm) δ 26.2. MS-ESI: m/z 240.8, [M +Na]+. O,O-Diisopropyl S-Phenyl Phosphorothioate (4h) (CAS Registry No. 15267-38-6).6

Yield: 58.4 mg,

71% (Method A); 57.4 mg, 70% (Method B). Yellow oil. 1H NMR (400 MHz, CDCl3, ppm) (Method B) δ 7.61 – 7.58 (m, 2 H), 7.35 – 7.32 (m, 3 H), 4.80 – 4.72 (m, 2 H), 1.32 (d, J = 6.2 Hz, 6 H), 1.25 (d, J = 6.2 Hz, 6 H). 13C{1H} NMR (100 MHz, CDCl3, ppm) δ 134.3 (d, J = 5.3 Hz), 129.2 (d, J = 1.8 Hz), 128.7 (d, J = 2.4 Hz), 127.4 (d, J = 7.0 Hz), 73.4 (d, J = 6.8 Hz), 23.9 (d, J = 4.2 Hz), 23.6 (d, J = 5.7 Hz). 31P{1H} NMR (162 MHz, CDCl3, ppm) δ 20.4. MS-ESI: m/z 297.0, [M + Na]+. O-Ethyl S-Phenyl Phenylphosphonothioate (4i) (CAS Registry No. 1629085-78-4).6 Yield: 61.7 mg, 74% (Method A); 55.9 mg, 67%, (Method B). Yellow oil. 1H NMR (400 MHz, CDCl3, ppm) (Method B) δ 7.67 – 7.62 (m, 2 H), 7.50 – 7.46 (m, 1 H), 7.38 – 7.33 (m, 2 H), 7.30 – 7.26 (m, 3 H), 7.19 (t, J = 7.7 Hz, 2 H), 4.42 – 4.22 (m, 2 H), 1.41 – 1.38 (m, 3 H). 13C{1H} NMR (100 MHz, CDCl3, ppm) δ 135.5 (d, J = 4.2 Hz), 132.5 (d, J = 3.1 Hz), 131.5 (d, J = 10.6 Hz), 131.6 (d, J = 151.3 Hz), 129.2 (d, J = 2.1 Hz), 129.0 (d, J = 2.7 Hz), 128.3 (d, J = 15.0 Hz), 126.7 (d, J = 5.6 Hz), 62.5 (d, J = 6.9 Hz), 16.4 (d, J = 6.8 Hz). 31P{1H} NMR (162 MHz, CDCl3, ppm) δ 41.7. MS-ESI: m/z 278.8, [M + H]+. S-Phenyl Diphenylphosphinothioate (4j) (CAS Registry No. 5510-78-1).5g Yield: 60.4 mg, 65% (Method A); 20.5 mg, 22% (Method B). White solid. 1H NMR (400 MHz, CDCl3, ppm) (Method B) δ 7.87 – 7.82 (m, 4 H), 7.56 – 7.38 (m, 8 H), 7.26 – 7.17 (m, 3 H). 13C{1H} NMR (100 MHz, CDCl3, ppm) δ 135.5 (d, J = 4.0 Hz), 132.7 (d, J = 106.8 Hz), 132.4 (d, J = 2.9 Hz), 131.7 (d, J = 10.2 Hz), 129.2 (d, J = 1.2 Hz), 129.0 (d, J = 1.8 Hz), 128.6 (d, J = 13.2 Hz), 126.3 (d, J = 5.3 Hz).

31

P{1H}

NMR (162 MHz, CDCl3, ppm) δ 41.4. MS-ESI: m/z 333.1, [M + Na]+. O,O-Diethyl S-(4-Fluorophenyl)phosphorothioate (4k) (CAS Registry No. 333-42-6).6 Yield: 71.2 mg,


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90% (Method A); 74.4 mg, 94% (method B). Yellow oil. 1H NMR (400 MHz, CDCl3, ppm) (Method B) δ 7.54 – 7.50 (m, 2 H), 7.03 (t, J = 8.5 Hz, 2 H), 4.23 – 4.10 (m, 4 H), 1.30 – 1.27 (m, 6 H). 13C{1H} NMR (100 MHz, CDCl3, ppm) δ 163.4 (dd, J = 250.0 Hz, J = 2.7 HZ), 136.8 (dd, J = 8.4 Hz, J = 4.9 Hz), 121.8 (dd, J = 7.3 Hz, J = 3.0 Hz), 116.7 (dd, J = 22.1 Hz, J = 1.9 Hz), 64.3 (d, J = 6.3 Hz), 16.1 (d, J = 7.1 Hz). 31P{1H} NMR (162 MHz, CDCl3, ppm) δ 22.6. 19F{1H} NMR (377 MHz, CDCl3, ppm) δ -111.6 (d, J = 4.9 Hz). MS-ESI: m/z 286.8, [M + Na]+. S-(4-Chlorophenyl) O,O-Diethyl Phosphorothioate (4l) (CAS Registry No. 4524-70-3).6 Yield: 73.1 mg, 87% (Method A); 78.1 mg, 93% (Method B). Yellow oil. 1H NMR (400 MHz, CDCl3, ppm) (Method B) δ 7.52 – 7.49 (m, 2 H), 7.32 (d, J = 8.4 Hz, 2 H), 4.27 – 4.11 (m, 4 H), 1.34 – 1.30 (m, 6 H). 13C{1H} NMR (100 MHz, CDCl3, ppm) δ 135.8 (d, J = 5.2 Hz), 135.5 (d, J = 3.5 Hz), 129.6 (d, J = 2.2 Hz), 125.2 (d, J = 7.3 Hz), 64.3 (d, J = 6.3 Hz), 16.0 (d, J = 7.1 Hz). 31P{1H} NMR (162 MHz, CDCl3, ppm) δ 22.1. MS-ESI: m/z 302.9, [M + Na]+. S-(4-Bromophenyl) O,O-Diethyl Phosphorothioate (4m) (CAS Registry No. 15224-36-9).6 Yield: 85.8 mg, 88% (Method A); 87.5 mg, 90% (Method B). Yellow oil. 1H NMR (400 MHz, CDCl3, ppm) (Method B) δ 7.49 – 7.42 (m, 4 H), 4.27 – 4.11 (m, 4 H), 1.33 – 1.30 (m, 6 H).

13

C{1H} NMR (100

MHz, CDCl3, ppm) δ 136.0 (d, J = 5.3 Hz), 132.5 (d, J = 2.0 Hz), 125.8 (d, J = 7.3 Hz), 123.6 (d, J = 3.6 Hz), 64.3 (d, J = 6.4 Hz), 16.0 (d, J = 7.0 Hz).

31

P{1H} NMR (162 MHz, CDCl3, ppm) δ 21.9.

MS-ESI: m/z 346.9, [M + Na]+. Ethyl 4-((Diethoxyphosphoryl)thio)benzoate (4n) . Yield: 89.6 mg, 94% (Method A); 83.0 mg, 87% (Method B). Yellow oil. 1H NMR (400 MHz, CDCl3, ppm) (Method B) δ 8.01 (d, J = 8.2 Hz, 2 H), 7.66 – 7.64 (m, 2 H), 4.41 – 4.36 (m, 2 H), 4.29 – 4.13 (m, 4 H), 1.39 (t, J = 7.1 Hz, 3 H), 1.34 – 1.30 (m, 6 H). 13C{1H} NMR (100 MHz, CDCl3, ppm) δ 165.8, 133.7 (d, J = 5.7 Hz), 132.8 (d, J = 7.0 Hz), 130.8



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(d, J = 3.0 Hz), 130.2 (d, J = 1.6 Hz), 64.4 (d, J = 6.4 Hz), 61.3, 16.0 (d, J = 7.2 Hz), 14.3.

Page 16 of 23

31

P{1H}

NMR (162 MHz, CDCl3, ppm) δ 21.4. HRMS (ESI) m/z: [M + Na]+ Calcd for C13H19NaO5PS+, 341.0583; Found: 341.0575). O,O-Diethyl S-(3-(Trifluoromethyl)phenyl) Phosphorothioate(4o) (CAS Registry No. 38726-06-6).6 Yield: 82.0 mg, 87% (Method A). Yellow oil. 1H NMR (400 MHz, CDCl3, ppm) δ 7.81(s, 1 H), 7.47 (d, J = 7.9 Hz, 1 H), 7.76 (d, J = 7.8 Hz, 1 H), 7.60 (t, J = 7.8 Hz, 1 H), 4.25 – 4.13 (m, 4 H), 1.31 – 1.28 (m, 6 H). 13C{1H} NMR (100 MHz, CDCl3, ppm) δ 137.9 (d, J = 5.2 Hz), 131.8 (dd, J = 32.8 Hz, J = 1.8 Hz), 131.4 – 131.2 (m), 129.88 (d, J = 2.7 Hz), 128.4 (d, J = 7.1 Hz), 125.8 (q, J = 3.28 Hz), 123.6 (d, J = 272.5 Hz), 64.5 (d, J = 6.4 Hz), 16.0 (d, J = 7.2 Hz). 31P{1H} NMR (162 MHz, CDCl3, ppm) δ 21.6. 19F NMR (377 MHz, CDCl3, ppm) δ -62.9. MS-ESI: m/z 337.0, [M + Na]+. O,O-Diethyl S-o-Tolyl Phosphorothioate (4p) (CAS Registry No. 94583-02-5).6 Yield: 56.9 mg, 73% (Method A); 57.7 mg, 74% (Method B). Yellow oil. 1H NMR (400 MHz, CDCl3, ppm) (Method B) δ 7.60 (d, J = 8.2 Hz, 1 H), 7.26 – 7.24 (m, 2 H), 7.20 – 7.15 (m, 1 H), 4.23 – 4.08 (m, 4 H), 2.52 (d, J = 1.0 Hz, 3 H), 1.31 – 1.27 (m, 6 H).

13

C{1H} NMR (100 MHz, CDCl3, ppm) δ 142.2 (d, J = 5.4 Hz),

136.2 (d, J = 4.0 Hz), 130.9 (d, J = 2.6 Hz), 129.5 (d, J = 2.9 Hz), 126.8 (d, J = 2.5 Hz), 125.8 (d, J = 7.4 Hz), 64.2 (d, J = 6.7 Hz), 21.4, 16.1 (d, J = 7.1 Hz). 31P{1H} NMR (162 MHz, CDCl3, ppm) δ 23.0. MS-ESI: m/z 283.0, [M + Na]+. O,O-Diethyl S-m-Tolyl Phosphorothioate (4q) (CAS Registry No. 108481-79-4).6 Yield: 65.5mg, 84% (Method A); 59.3 mg, 76% (Method B). Yellow oil. 1H NMR (400 MHz, CDCl3, ppm) (Method B) δ 7.37 (d, J = 10.3 Hz, 2 H), 7.22 (d, J = 7.6 Hz, 1 H), 7.16 (d, J = 7.6 Hz, 1 H), 4.28 – 4.11 (m, 4 H), 2.34 (s, 3 H), 1.33 – 1.29 (m, 6 H). 13C{1H} NMR (100 MHz, CDCl3, ppm) δ 139.3 (d, J = 2.2 Hz), 135.2 (d, J = 5.2 Hz), 131.6 (d, J = 5.2 Hz), 129.9 (d, J = 2.8 Hz), 129.2 (d, J = 2.1 Hz), 126.2 (d, J =


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7.2 Hz), 64.1 (d, J = 6.1 Hz), 21.3, 16.0 (d, J = 7.2 Hz). 31P{1H} NMR (162 MHz, CDCl3, ppm) δ 23.1. MS-ESI: m/z 282.9, [M + Na]+. S-[1,1'-Biphenyl]-4-yl O,O-Diethyl Phosphorothioate (4r). Yield: 67.6 mg, 70% (method A). Yellow oil. 1

H NMR (400 MHz, CDCl3, ppm) δ 7.64 – 7.62 (m, 2 H), 7.57 (d, J = 7.8 Hz, 4 H), 7.44 (t, J = 7.6 Hz,

2 H), 7.38 – 7.35 (m, 1 H), 4.29 – 4.16 (m, 4 H), 1.35 – 1.32 (m, 6 H).

13

C{1H} NMR (100 MHz,

CDCl3, ppm) δ 142.1 (d, J = 3.0 Hz), 140.0, 135.0 (d, J = 5.3 Hz), 129.0, 128.1 (d, J = 2.0 Hz), 127.9, 127.2, 125.4 (d, J = 7.3 Hz), 64.2 (d, J = 6.1 Hz), 16.2 (d, J = 7.2 Hz).

31

P{1H} NMR (162 MHz,

CDCl3, ppm) δ 22.8. HRMS (ESI) m/z: [M + Na]+ Calcd for C16H19NaO3PS+, 345.0685; Found: 345.0669). O,O-Diethyl S-(2-Fluorophenyl) Phosphorothioate (4s) (CAS Registry No. 1883501-47-0).6 Yield: 61.0 mg, 77% (Method B). Yellow oil. 1H NMR (400 MHz, CDCl3, ppm) (Method A) δ 7.64 – 7.60 (m, 1 H), 7.41 – 7.35 (m, 1 H), 7.17 – 7.11 (m, 2 H), 4.30 – 4.16 (m, 4 H), 1.34 – 1.31 (m, 6 H). 13C{1H} NMR (100 MHz, CDCl3, ppm) δ 162.7 (dd, J = 248.8 Hz, J = 5.6 Hz), 137.6 (d, J = 4.3 Hz), 131.7 (dd, J = 8.0 Hz, J = 2.76), 124.9-125.0 (m), 116.4 (dd, J = 22.9 Hz, J = 2.3 Hz), 113.9 (dd, J = 18.5 Hz, J = 7.5 Hz), 64.3 (d, J = 6.0 Hz), 16.0 (d, J = 7.0 Hz). 31P{1H} NMR (162 MHz, CDCl3, ppm) δ 21.3 (d, J = 2.8 Hz). 19F NMR (377 MHz, CDCl3, ppm) δ -106.2 (d, J = 4.0 Hz). MS-ESI: m/z 286.8, [M + Na]+. S-(2-Chlorophenyl) O,O-Diethyl Phosphorothioate (4t) (CAS Registry No. 15224-41-6).6 Yield: 62.2 mg, 74% (Method B). Yellow oil. 1H NMR (400 MHz, CDCl3, ppm) δ 7.76 (d, J = 7.5 Hz, 1 H), 7.46 (d, J = 7.6 Hz, 1 H), 7.32 – 7.24 (m, 2 H), 4.30 – 4.16 (m, 4 H), 1.34 – 1.30 (m, 6 H). 13C{1H} NMR (100 MHz, CDCl3, ppm) δ 137.9 (d, J = 6.9 Hz), 136.8 (d, J = 4.0 Hz), 130.3 (d, J = 6.7 Hz), 127.5, 126.4 (d, J = 6.8 Hz), 64.4 (d, J = 6.3 Hz), 16.0 (d, J = 7.3 Hz). 31P{1H} NMR (162 MHz, CDCl3, ppm) δ 21.2. MS-ESI: m/z 302.9, [M + Na]+.



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Page 18 of 23

O,O-Diethyl S-(2-Iodophenyl) Phosphorothioate (4u). Yield: 87.0 mg, 78% (Method B). Yellow oil. 1H NMR (400 MHz, CDCl3, ppm) δ 7.90 (d, J = 8.0 Hz, 1 H), 7.83 – 7.80 (m, 1 H), 7.37 – 7.33 (m, 1 H), 7.02 (t, J = 7.7 Hz, 1 H), 4.31 – 4.16 (m, 4 H), 1.34 – 1.30 (m, 6 H). 13C{1H} NMR (100 MHz, CDCl3, ppm) δ 140.2 (d, J = 2.1 Hz), 135.3 (d, J = 4.0 Hz), 132.9 (d, J = 6.7 Hz), 130.2, 129.1 (d, J = 2.0 Hz), 105.6 (d, J = 8.1 Hz), 64.5 (d, J = 6.4 Hz), 16.1 (d, J = 7.2 Hz). 31P{1H} NMR (162 MHz, CDCl3, ppm) δ 21.6. HRMS (ESI) m/z: [M + Na]+ Calcd for C10H15IO3PS+, 372.9519; Found: 372.9515). S-(2-Bromophenyl) O,O-Diethyl phosphorothioate (4v) (CAS Registry No. 1807788-31-3).5j Yield: 85.5 mg, 88% (Method B). Yellow oil. 1H NMR (400 MHz, CDCl3, ppm) δ 7.71 – 7.69 (m, 1 H), 7.51 – 7.46 (m, 2 H), 7.21 (t, J = 7.9 Hz, 1 H), 4.26 – 4.11 (m, 4 H), 1.33 – 1.29 (m, 6 H). 13C{1H} NMR (100 MHz, CDCl3, ppm) δ 137.0 (d, J = 5.3 Hz), 133.0 (d, J = 5.3 Hz), 132.1 (d, J = 2.7 Hz), 130.6 (d, J = 2.1 Hz), 128.8 (d, J = 7.0 Hz), 122.7 (d, J = 2.7 Hz), 64.3 (d, J = 6.4 Hz), 16.0 (d, J = 7.1 Hz). 31P{1H} NMR (162 MHz, CDCl3, ppm) δ 21.77. MS-ESI: m/z 346.9, [M + Na]+. S-(4-Cyanophenyl) O,O-Diethyl Phosphorothioate (4w) (CAS Registry No. 179637-16-2).6 Yield: 75.5 mg, 93% (Method B). Yellow oil. 1H NMR (400 MHz, CDCl3, ppm) δ 7.69 – 7.67 (m, 2 H), 7.61 (d, J = 8.2 Hz, 2 H), 4.25 – 4.14 (m, 4 H), 1.32 – 1.30 (m, 6 H). 13C{1H} NMR (100 MHz, CDCl3, ppm) δ 134.2 (d, J = 6.0 Hz), 134.0 (d, J = 6.7 Hz), 132.7, 118.0, 112.5 (d, J = 2.3 Hz), 64.7 (d, J = 6.5 Hz), 16.0 (d, J = 6.9 Hz). 31P{1H} NMR (162 MHz, CDCl3, ppm) δ 20.3. MS-ESI: m/z 294.0, [M + Na]+. S-(4-Acetylphenyl) O,O-Diethyl Phosphorothioate (4x) (CAS Registry No. 1883501-44-7).6 Yield: 78.6 mg, 91% (Method B). Yellow oil. 1H NMR (400 MHz, CDCl3, ppm) δ 7.88 (d, J = 8.3 Hz, 2 H), 7.65 – 7.63 (m, 2 H), 4.25 – 4.11 (m, 4 H), 2.56 (s, 3 H), 1.30 – 1.27 (m, 6 H).

13

C{1H} NMR (100 MHz,

CDCl3, ppm) δ 197.2 (s), 137.0, 133.9 (d, J = 5.8 Hz), 133.2 (d, J = 6.9 Hz), 129.0 (d, J = 1.2 Hz), 64.4 (d, J = 6.4 Hz), 26.7, 16.0 (d, J = 7.0 Hz). 31P{1H} NMR (162 MHz, CDCl3, ppm) δ 21.2. MS-ESI: m/z


Page 19 of 23

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310.8, [M + Na]+. O,O-Diethyl S-(4-(Trifluoromethyl)phenyl) Phosphorothioate (4y) (CAS Registry No. 1883501-42-5).6 Yield: 84.8 mg, 90% (method B). Yellow oil. 1H NMR (400 MHz, CDCl3, ppm) δ 7.70 (d, J = 7.8 Hz, 2 H), 7.60 (d, J = 8.4 Hz, 2 H), 4.28 – 4.13 (m, 4 H), 1.34 – 1.30 (m, 6 H).

13

C{1H} NMR (100 MHz,

CDCl3, ppm) δ 134.3 (d, J = 5.6 Hz), 132.0 (d, J = 6.6 Hz), 131.0 (m, J = 17.7.0 Hz), 126.2, 123.8 (d, J = 272.1 Hz), 64.5 (d, J = 6.4 Hz), 16.0 (d, J = 7.1 Hz). 31P{1H} NMR (162 MHz, CDCl3, ppm) δ 21.3. 19

F{1H} NMR (377 MHz, CDCl3, ppm) δ -62.9. MS-ESI: m/z 336.9, [M + Na]+.

O,O-Diethyl S-(4-Nitrophenyl) Phosphorothioate (4z). Yield: 71.6 mg, 82% (Method B). Yellow oil. 1H NMR (400 MHz, CDCl3, ppm) δ 8.20 (d, J = 8.6 Hz, 2 H), 7.78 – 7.75 (m, 2 H), 4.32 – 4.15 (m, 4 H), 1.36 – 1.33 (m, 6 H). 13C{1H} NMR (100 MHz, CDCl3, ppm) δ 147.9, 136.3 (d, J = 6.5 Hz), 134.2 (d, J = 6.0 Hz), 124.2, 64.8 (d, J = 6.4 Hz), 16.1 (d, J = 7.0 Hz). 31P{1H} NMR (162 MHz, CDCl3, ppm) δ 19.8. HRMS (ESI) m/z: [M + Na]+ Calcd for C10H14NaNO5PS+, 314.0223; Found: 314.0218). S-(4-Carbamoylphenyl) O,O-Diethyl Phosphorothioate (4aa). Yield: 57.2 mg, 66% (method B). Yellow solid, m.p. 144.5-146.8 oC. 1H NMR (400 MHz, CDCl3, ppm) δ 7.78 (d, J = 8.0 Hz, 2 H), 7.64 (t, J = 4.1 Hz, 2 H), 6.33 (s, 1 H), 5.89 (s, 1 H), 4.26 – 4.13 (m, 4 H), 1.33 – 1.30 (m, 6 H); 13C{1H} NMR (100 MHz, CDCl3, ppm) δ 168.6, 134.3 (d, J = 5.4 Hz), 133.9 (d, J = 2.6 Hz), 131.6 (d, J = 6.6 Hz), 128.3, 64.6 (d, J = 6.4 Hz), 16.1 (d, J = 7.0 Hz);

31

P{1H} NMR (162 MHz, CDCl3, ppm) δ 21.7.

HRMS-ESI: m/z found: 312.0415 ([M + Na]+, C11H16NaNO4PS+ calcd. 312.0430). S-(3,5-Dimethylphenyl) O,O-Diethyl Phosphorothioate (4ab) (CAS Registry No. 1883501-37-8).6 Yield: 51.8 mg, 63% (Method B). Yellow oil. 1H NMR (400 MHz, CDCl3, ppm) δ 7.17 (s, 2 H), 6.97 (s, 1 H), 4.24 – 4.12 (m, 4 H), 2.29 (s, 6 H), 1.32-1.29 (m, 6 H). 13C{1H} NMR (100 MHz, CDCl3, ppm) δ 139.1 (d, J = 2.0 Hz), 132.3 (d, J = 5.2 Hz), 131.0 (d, J = 2.8 Hz), 125.8 (d, J = 7.1 Hz), 64.1 (d, J = 6.2 Hz),



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21.3, 16.1 (d, J = 7.3 Hz). 31P{1H} NMR (162 MHz, CDCl3, ppm) δ 23.4. MS-ESI: m/z 296.8, [M + Na]+.

ASSOCIATED CONTENT Acknowledgements We acknowledge financial support from the Chinese National Natural Science Foundation (21232005, 21375113), the National Basic Research Program of China (2012CB821600), and the Fundamental Research Funds for the Central Universities (20720160030). Supporting Information. Copies of 1H NMR, 13C NMR spectra of compounds 4a-4z and 4aa-4ab. The Supporting Information is available free of charge on the ACS Publications website.

References

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